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1.
2.
Oxygen- and temperature-dependent cytotoxic and radiosensitizing effects of cis-dichlorodiammineplatinum(II) on human NHIK 3025 cells in vitro 总被引:1,自引:0,他引:1
The radiosensitizing effect of the chemotherapeutic drug cis-dichlorodiammineplatinum(II) (cis-DDP) was tested on human NHIK 3025 cells cultivated in vitro. cis-DDP was found to exert a radiomodifying effect under hypoxic but not under aerobic conditions. These results confirm that cis-DDP may act as a radiosensitizer of hypoxic cells; however, the radiosensitizing effect was seen only at concentrations of cis-DDP having a considerable cytotoxic activity, and for practical reasons concerning survival level the highest drug concentration that was investigated was 15 microM at 37 degrees C. The radiosensitizing effect was of a dose-modifying type and with a dose-modifying factor (DMF) of 1.2 at 15 microM in hypoxic cells. The radiosensitizing as well as the cytotoxic effect of cis-DDP was found to be strongly temperature dependent. Isoeffect doses of cis-DDP was reduced with a factor of 3 at 22 as compared to 37 degrees C. We also found that hypoxic cells were less sensitive to cis-DDP than cells treated in the presence of oxygen. To test the correlation between cytotoxicity and radiosensitization on the one hand and cellular uptake of cis-DDP on the other, cell-associated Pt was measured by atomic absorption spectroscopy. From these studies the cytotoxicity of cis-DDP at 22 and 37 degrees C under aerobic conditions was found to be the same as long as the amount of cell-associated Pt (i.e., the cellular uptake) was the same. However, whether the cells were treated under hypoxic or aerobic conditions, the cellular uptake of Pt was the same. While the radiosensitizing effect was present at 37 and at 40 degrees C, no such effect could be found at 22 degrees C. Since the cytotoxicity of cis-DDP as well as the drug uptake was reduced about three times at 22 as compared to 37 degrees C, we increased the concentration threefold, to 50 microM at 22 degrees C. Still no radiosensitizing effect was found at this temperature. 相似文献
3.
Sissel Rogne
ystein W. Rnning Ola Myklebost Per O. Seglen Erik O. Pettersen 《Journal of cellular physiology》1985,125(3):528-532
We have studied the effect of cell anchorage on the human cell line NHIK 3025 in vitro, to see whether the growth regulating effect of cell anchorage primarily affected DNA division cycle or mass growth cycle. It was found that cell to cell anchorage had the same effect on cell cycle progression as anchorage to a solid surface, which indicates that it is anchorage per se and not cell shape that is important for growth control in NHIK 3025 cells. When NHIK 3025 cells were grown without attachment to a solid surface, both G1 and cell cycle duration was prolonged by 6 h, which means that the prolonged cell cycle was due to a prolonged G1. During the first part of the cell cycle the rate of protein synthesis and degradation was constant, and at the same level in cells grown with and without attachment. This means that the prolonged G1 was not due to a reduced protein accumulation or mass growth. Towards the end of the cell cycle protein accumulation was reduced. This effect was either due to a size control before cell division or a secondary effect of the prolonged G1. We therefore conclude that cell anchorage as a growth regulator primarily affects the DNA/cell division cycle. 相似文献
4.
The mitotic inhibitor 1-propargyl-5-chloropyrimidin-2-one (a metahalone) was found to bind to DEAE-cellulose purified rat brain tubulin. A decrease in the fluorescence of 1-propargyl-5-chloropyrimidin-2-one was seen when the drug was incubated in the presence of increasing tubulin concentrations. The decrease in metahalone fluorescence was not affected by the addition of GTP, indicating drug interaction at other portions of the tubulin molecule than the nucleotide binding sites. Scatchard plot analysis following incubation of tubulin with 1-propargyl-5-chloro-[2-14C]pyrimidin-2-one revealed that 1 mol of metahalone bound to 1 mol of tubulin dimer with a measured association constant of 8.0 X 10(3) M-1. Double reciprocal plots of vincristine and colchicine binding to tubulin in the presence of 1-propargyl-5-chloropyrimidin-2-one showed that the metahalone competitively inhibited colchicine binding to tubulin but had no influence on vincristine binding. This conclusion was supported by gel filtration chromatography where an increase in unbound colchicine was measured when 1-propargyl-5-chloropyrimidin-2-one was present in an incubation mixture containing colchicine and tubulin. In the presence of 5 mM 1-propargyl-5-chloropyrimidin-2-one, tubulin self-aggregated into crystalline structures. The binding of 1-propargyl-5-chloropyrimidin-2-one to tubulin at or near the colchicine binding site may be responsible for the metaphase arresting characteristics of this drug. 相似文献
5.
- The transport of guanine in autospores of light-dark synchronizedChlorella fusca was studied using radioactive guanine in the concentration range of 4 nM to 50 μM.
- The transport system was constitutive, it had high specificity for the permeant, and theQ 10 value was in the range of 1.5 to 2.2. At concentrations lower than 0.2 μM the half saturating constant, S0.5 was 1 μM both for cells kept in dark and cells kept in light. At higher concentrations the S0.5 of darkened cells was about 0.23 μM, while that of illuminated cells was unchanged. Only above 0.2 μM guanine did illumination of the cells or addition of glucose increase the transport rate.
- Guanine which had accumulated did not leak out at temperatures below 45°C or by treatment with 10 μM dinitrophenol, which completely inhibited transport. Furthermore, the accumulated guanine did not exchange with exogenous guanine.
- The guanine accumulated, more than 105-fold over the external concentration, showing that the transport, was active.
- The initial transport rate per cell revealed annual fluctuations.
6.
ystein W. Rnning Tore Lindmo Erik O. Pettersen Per O. Seglen 《Journal of cellular physiology》1981,107(1):47-57
Human NHIK 3025 cells growing exponentially in 30% or 3% serum had population doubling times of 19.1 and 27.6 hours, respectively. These values were equal to the calculated protein doubling times (17.6 and 26.5 hours, respectively), showing that the cells were in balanced growth at both serum concentrations. Stepdown from 30% to 3% serum reduced the rate of protein synthesis within 1–2 hours, from 5.7% hour to 4.3% hour, while the rate of protein degradation was unchanged (1.7%/hour). In cells synchronized by mitotic selection from an exponentially growing population, the median cell cycle durations in 30% and 3% serum were 17.2 and 23.6 hours, respectively, which were also in good agreement with the protein doubling times. The median G1 durations were 7.1 and 9.6 hours, respectively. Thus the duration of G1 relative to the total cell cycle duration was the same in the two cases. Complete removal of serum for a period of 3 hours resulted in a 3-hour prolongation of the cell cycle regardless of the time after mitotic selection at which the serum was removed. For synchronized cells, the rate of entry into both the S phase and into the subsequent cell cycle were reduced in 3% serum as compared to 30% serum, the former rate being significantly greater than the latter at both serum concentrations. Our results thus indicate that these cells are continuously dependent upon serum throughout the entire cell cycle. 相似文献
7.
Summary The purpose of this study was to examine whether formal-dehyde-fixed tissue may afford reproducible and reliable immunhistochemical results when carcinoembryonic antigen (CEA), secretory component (SC), and epithelial IgA are evaluated semiquantitatively in normal and pathological colon specimens. Proximate tissue samples were processed by routine formalin fixation and by a cold-ethanol fixation method, respectively, and the immunofluorescence intensities obtained for the three antigens were scored. After formalin fixation SC and epithelial IgA were generally undetectable and also the staining for CEA was markedly reduced compared with that seen after ethanol fixation. Significant antigenic unmasking was obtained by enzyme treatment of the formalin-fixed tissue sections-resulting in enhanced staining for SC and epithelial IgA but not consistently so for CEA. With this modification scores from duplicate tissue samples processed by the two methods showed significant correlations for all the three epithelial markers; small amounts of CEA and epithelial IgA, and especially SC, nevertheless remained undetectable after formalin fixation. This result should be taken into account when epithelial markers are applied in studies of premalignant lesions of the colon where minor changes in the antigen pattern may be of diagnostic importance. 相似文献
8.
Turid Hellevik Ingvild Pettersen Vivian Berg Jack Bruun Kristian Bartnes Lill-Tove Busund Anthony Chalmers Roy Bremnes Iñigo Martinez-Zubiaurre 《Translational oncology》2013,6(1):66-74
In the context of radiotherapy, collateral effects of ablative doses of ionizing radiation (AIR) on stromal components of tumors remains understudied. In this work, cancer-associated fibroblasts (CAFs) isolated from freshly resected human lung tumors were exposed to AIR (1x 18 Gy) and analyzed for their release of paracrine factors. Inflammatory mediators and regulators of angiogenesis and tumor growth were analyzed by multiplex protein assays in conditioned medium (CM) from irradiated and non-irradiated CAFs. Additionally, the profile of secreted proteins was examined by proteomics. In functional assays, effects of CAF-CM on proliferative and migratory capacity of lung tumor cells (H-520/H-522) and human umbilical vein endothelial cells (HUVECs) and their tube-forming capacity were assessed. Our data show that exposure of CAFs to AIR results in 1) downregulated release of angiogenic molecules such as stromal cell-derived factor-1, angiopoietin, and thrombospondin-2 (TSP-2); 2) upregulated release of basic fibroblast growth factor from most donors; and 3) unaffected expression levels of hepatocyte growth factor, interleukin-6 (IL-6), IL-8, IL-1β, and tumor necrosis factor-α. CM from irradiated and control CAFs did not affect differently the proliferative or migratory capacity of tumor cells (H-520/H-522), whereas migratory capacity of HUVECs was partially reduced in the presence of irradiated CAF-CM. Overall, we conclude that AIR mediates a transformation on the secretory profile of CAFs that could influence the behavior of other cells in the tumor tissue and hence guide therapeutic outcomes. Downstream consequences of the changes observed in this study merits further investigations. 相似文献
9.
Szymon ??ski Henrik Lindén Tom Tetzlaff Klas H. Pettersen Gaute T. Einevoll 《PLoS computational biology》2013,9(7)
Despite its century-old use, the interpretation of local field potentials (LFPs), the low-frequency part of electrical signals recorded in the brain, is still debated. In cortex the LFP appears to mainly stem from transmembrane neuronal currents following synaptic input, and obvious questions regarding the ‘locality’ of the LFP are: What is the size of the signal-generating region, i.e., the spatial reach, around a recording contact? How far does the LFP signal extend outside a synaptically activated neuronal population? And how do the answers depend on the temporal frequency of the LFP signal? Experimental inquiries have given conflicting results, and we here pursue a modeling approach based on a well-established biophysical forward-modeling scheme incorporating detailed reconstructed neuronal morphologies in precise calculations of population LFPs including thousands of neurons. The two key factors determining the frequency dependence of LFP are the spatial decay of the single-neuron LFP contribution and the conversion of synaptic input correlations into correlations between single-neuron LFP contributions. Both factors are seen to give low-pass filtering of the LFP signal power. For uncorrelated input only the first factor is relevant, and here a modest reduction (<50%) in the spatial reach is observed for higher frequencies (>100 Hz) compared to the near-DC () value of about . Much larger frequency-dependent effects are seen when populations of pyramidal neurons receive correlated and spatially asymmetric inputs: the low-frequency () LFP power can here be an order of magnitude or more larger than at 60 Hz. Moreover, the low-frequency LFP components have larger spatial reach and extend further outside the active population than high-frequency components. Further, the spatial LFP profiles for such populations typically span the full vertical extent of the dendrites of neurons in the population. Our numerical findings are backed up by an intuitive simplified model for the generation of population LFP. 相似文献
10.
Benjamin D. Stevens John Litchfield Jeffrey A. Pfefferkorn Karen Atkinson Christian Perreault Paul Amor Kevin Bahnck Martin A. Berliner Jessica Calloway Anthony Carlo David R. Derksen Kevin J. Filipski Mike Gumkowski Charanjeet Jassal Margit MacDougall Brendan Murphy Paul Nkansah John Pettersen Yan Zhang 《Bioorganic & medicinal chemistry letters》2013,23(24):6588-6592
Glucokinase (hexokinase IV) continues to be a compelling target for the treatment of type 2 diabetes given the wealth of supporting human genetics data and numerous reports of robust clinical glucose lowering in patients treated with small molecule allosteric activators. Recent work has demonstrated the ability of hepatoselective activators to deliver glucose lowering efficacy with minimal risk of hypoglycemia. While orally administered agents require a considerable degree of passive permeability to promote suitable exposures, there is no such restriction on intravenously delivered drugs. Therefore, minimization of membrane diffusion in the context of an intravenously agent should ensure optimal hepatic targeting and therapeutic index. This work details the identification a hepatoselective GKA exhibiting the aforementioned properties. 相似文献